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Advanced Drug Delivery Reviews

Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides

Advanced Drug Delivery Reviews, 2015 · Cited by 863 papers · doi:10.1016/j.addr.2015.01.008

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What this article backs

• Phosphorothioate Backbone Modification ↑ Plasma Protein Binding
• Plasma Protein Binding ↑ Tissue Bioavailability
• Sugar 2 Prime Position Modification ↑ Antisense Oligonucleotide Potency
• Blood Brain Barrier ✕ Antisense Oligonucleotide Cns Distribution
• Intrathecal Administration ✚ Antisense Oligonucleotide Cns Distribution

• Phosphorothioate Backbone Modification increases Plasma Protein Binding.
• Plasma Protein Binding increases Tissue Bioavailability.
• Sugar 2 Prime Position Modification increases Antisense Oligonucleotide Potency.
• Blood Brain Barrier prevents Antisense Oligonucleotide Cns Distribution.
• Intrathecal Administration enables Antisense Oligonucleotide Cns Distribution.

In its own words

Additional modifications of the sugar at the 2' position, increase RNA binding affinity and significantly increase potency, tissue half-life and prolong RNA inhibitory activity.

The substitution of one non-bridging oxygen with the more hydrophobic sulfur atom (phosphorothioate) increases both plasma stability and plasma protein binding

modified single-strand oligonucleotides administered by intrathecal injection into the CSF distribute broadly in the CNS.

plasma protein binding that limits glomerular filtration and ultimate urinary excretion of oligonucleotides

Both size and charge for most oligonucleotides prevents distribution across the blood brain barrier.